Both NMDA hypofunction and dopamine hyperfunction have been implicated in Schizophrenia. Moreover,[unreadable] the hippocampal region appears to be involved in the disease, perhaps because of aberrant novelty[unreadable] detection processes in the CA1 region. These novelty detection processes may depend on predictions[unreadable] arriving at CA1 from CAS via the Schaffer collaterals (SC) and sensory reality arriving directly from cortex via[unreadable] the perforant path (PP). It is therefore important to understand dopamine and NMDAR function in CA1, to[unreadable] elucidate the ways in which they contribute to pathway interactions, and to test the hypothesis that these[unreadable] pathway interactions indeed underlie a novelty detection process. Aim 1 seeks to understand the role of[unreadable] dopamine/NMDAR interactions at the SC and PP. Preliminary evidence indicates that D1 modulation can[unreadable] affect the NMDA conductance through a postsynaptic process, that the NMDA subunits are different in the[unreadable] two pathways and that D1 modulation may depend on NMDA subunit composition. This line of investigation[unreadable] will be continued and extended to D2 modulation. The ability to excite individual synapses using two-photon[unreadable] uncaging of glutamate will allow the first study of dopaminergic modulation at single dendritic spines. It will[unreadable] thus be possible to test whether this modulation is heterogeneous at the single spine level. Aim 2 utilizes[unreadable] both in vivo and in vitro approaches to test the hypothesis that pathway interactions perform a novelty[unreadable] detection process. Whole cell recording will be used to understand the biophysics of pathway interaction and[unreadable] the role of NMDAR and dopaminergic modulation in this process. Preliminary work suggests that pathway[unreadable] interactions can lead to supra-linear dendritic responses and that these are dependent on the NMDAR[unreadable] function. However, other work indicates that naturally occurring processes mediated by GABA conductances[unreadable] and lh can prevent (brake) the supralinearity. Experiments will be conducted to determine whether there are[unreadable] pathway timing conditions or neuromodulatory conditions in which the effectiveness of the brake is[unreadable] minimized. A supralinear response generated by an NMDA spike would be a candidate biophysical response[unreadable] to mediate novelty detection (a match signal). The role of dopamine in modulating these pathways (as[unreadable] studied in Aim 1) will also be examined. A critical need in understanding the pathway interactions studied in[unreadable] vitro is to obtain data about the CA1 computations that occur in vivo. In collaboration with the Center[unreadable] member, Howard Eichenbaum, recordings will be made from the CA1 region during the presentation of novel[unreadable] sequences. Multiple tetrodes will be used to test whether CA1 is a site of novelty detection, as proposed on[unreadable] theoretical grounds. Together these lines of investigation will help to integrate events spanning across[unreadable] multiple levels and elucidate how molecular defects in the NMDA and dopamine system could contribute to[unreadable] symptoms of schizophrenia.[unreadable]